Outcome Indicators Identified for Nivolumab Treatment of Patients With Metastatic Clear Cell Renal Cell Carcinoma

The predictive value provided by T effector (Teff) and angiogenesis (Angio) signatures were found to be augmented by Kidney Immune Classification (KIC) of tumor microenvironments, according to results presented at the ESMO Virtual Congress 2020. The researchers explained that the predictive value provided by the signatures was indicative of outcomes following treatment with nivolumab among patients with metastatic clear cell renal cell carcinoma (ccRCC).

After learning of a study that demonstrated the safety and efficacy of nivolumab for patients with metastatic ccRCC in a real-world setting, researchers from the Inflammation, Complement and Cancer at the Centre de Recherche des Cordeliers in Paris, France, were interested in pursuing the Kidney Immune Classification (KIC) project to investigate the opportunity provided by signatures.

During their presentation at the ESMO congress, the researchers explained that their study was intended to determine gene expression signatures and tumor microenvironments to assess the association with patient outcomes following treatment with nivolumab, with the additional aim of identifying biomarkers for nivolumab activity.

In the NIVOREN trial, the translational cohort from was comprised of 324 ccRCC formalin-fixed paraffin-embedded (FFPE) samples, with 184 being profiled by 3’ RNA sequencing. These 184 samples were then split in discovery (n=79) and validation (n=105) cohorts.

The researchers then assessed the impact of Teff and Angio signatures on patient outcomes using the median mRNA expression values. They performed an unsupervised analysis using the Microenvironment Cell Populations-Counter to classify tumors according to their infiltration by 8 immune and 2 stromal cell populations, with a focus toward identifying the characteristics of the tumor microenvironment.

Following this analysis, the researchers found that Angio and Teff signatures separately were not predictive of outcomes following nivolumab treatment. However, the combination of both signatures was very informative when identifying characteristics.

The researchers found that the signatures together revealed the most aggressive tumors, Teff-high/Angio-low and Teff-low/Angio-low, were associated with response rate (RR; best response determined by complete or partial response) and progression-free survival (PFS) in the discovery cohort.

Additionally, a favorable outcome was found to be indicated by a Teff-high/Angio-low signature, which was associated with a RR of 47% and median PFS of 10.1 months. However, the Teff-low/Angio-low signature was associated with poorer RR of 5% and median PFS of 2.6 months.

During the unsupervised classification process, the researchers were able to classify 5 KIC subtypes. These subtypes were designated from A to E. The KIC C+E tumors demonstrated high levels of CD8 positive cells and low numbers of stromal cells (CD8-high/S-low), but were associated with an improved RR and PFS compared with KIC A tumors (I-low/S-low), KIC B tumors (I-low/S-high), and KIC C tumors (I-high/S-high).

After evaluating the KIC classification, the researchers were able to identify tumor microenvironments that were associated with nivolumab outcomes in the discovery cohort. Specifically, KIC C-E was associated with a 48% RR and median PFS of 11.4 months, whereas KIC A-B-D was associated with a 15% RR and median PFS of just 2.8 months.

Among the validation cohort, the KIC classification was also found to be associated with nivolumab outcomes, with the KIC C-E displaying 36% RR and the KIC A-B-D 11% RR.

In tumors associated with the worst outcomes, a similar contribution of KIC stromal cells and the Angio signatures was present.

Since these results are from the first prospective trial of its kind, the authors noted that immune high/angiogenesis and stromal low signatures could potentially be predictive of the efficacy of nivolumab in patients with metastatic ccRCC.

Additionally, the authors explained that the results from this study demonstrate that KIC provides a first step in dismantling the impact of immunosuppression contributed by neutrophils, fibroblasts, and endothelial cells in the tumor microenvironment.

REFERENCE

Indicators of Outcome Are Identified for Nivolumab Treatment of Patients With Metastatic Clear Cell Renal Cell Carcinoma. Geneva, Switzerland: ESMO; September 21, 2020. esmo.org/meetings/esmo-virtual-congress-2020/meeting-resources/scientific-news/indicators-of-outcome-are-identified-for-nivolumab-treatment-of-patients-with-metastatic-clear-cell-renal-cell-carcinoma. Accessed September 23, 2020.